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US4740595A - Preparation of azetidinones via N-protected oxirancecarboxamide intermediates - Google Patents

Preparation of azetidinones via N-protected oxirancecarboxamide intermediates Download PDF

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Publication number
US4740595A
US4740595A US06/839,307 US83930786A US4740595A US 4740595 A US4740595 A US 4740595A US 83930786 A US83930786 A US 83930786A US 4740595 A US4740595 A US 4740595A
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formula
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produce
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Samuel Chackalamannil
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Merck Sharp and Dohme LLC
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Schering Corp
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Priority to US06/839,307 priority Critical patent/US4740595A/en
Assigned to SCHERING CORPORATION, A CORP. OF NEW JERSEY reassignment SCHERING CORPORATION, A CORP. OF NEW JERSEY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: CHACKALAMANNIL, SAMUEL
Priority to EP87302092A priority patent/EP0238252B1/de
Priority to ES198787302092T priority patent/ES2032201T3/es
Priority to DE8787302092T priority patent/DE3778946D1/de
Priority to AT87302092T priority patent/ATE76065T1/de
Priority to JP62056399A priority patent/JPS62221665A/ja
Priority to US07/127,844 priority patent/US4827006A/en
Publication of US4740595A publication Critical patent/US4740595A/en
Application granted granted Critical
Priority to US07/277,084 priority patent/US4963670A/en
Priority to US07/621,158 priority patent/US5089609A/en
Priority to GR920401693T priority patent/GR3005360T3/el
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to an improvement in a multistep stereospecific process for producing azetidinones which are useful as intermediates for preparing penems and carbapenems. More particularly, this invention relates to an improvement in the stereospecific multistep process in which L-threonine is converted to an epoxyamide containing a specific nitrogen protecting group, lower alkoxyphenylmethyl, preferably ethoxyphenylmethyl, cyclizing to form an azetidinone, then readily removing the protecting group under mild acidic conditions.
  • L-threonine is converted to (2S, 3R)-2-bromo-3-hydroxybutyric acid as disclosed for example in Yanagisawa, et al., Tetrahedron Letters 24 No. 10, 1037 (1984) or Izumiya, Bull. Chem. Soc. Japan, 26, 53 (1953).
  • the (2S, 3R)-2-bromo-3-hydroxybutyric acid is converted to an epoxyamide.
  • the epoxyamide is converted, by ring closure to an azetidinone in which the nitrogen is protected by a para-methoxyphenyl or a 2,4-dimethoxybenzyl group.
  • the former N-protecting group can be removed by the method disclosed in Kronenthal et al., J. Org. Chem., 47, 2765 (1982), i.e. by use of ceric ammonium nitrate. Another means of removing that N-protecting group is by ozonolysis in ethyl acetate.
  • the 2,4-dimethoxybenzyl group can be removed by use of potassium persulfate-dipotassium hydrogen phosphate in acetonitrile-water as disclosed by Huffman et al. J.A.C.S. 99, 2352 (1977).
  • This invention provides an improved process step in a multistep process for producing azetidinone intermediates for penems and carbapenems. More particularly, this invention provides the steps of producing azetidinones represented by the formula ##STR2## wherein R' is independently hydrogen, one, two, or three of halogen, lower alkyl or lower alkoxy, preferably hydrogen, from L-(-)-threonine in a multistep process utilizing as an N-protecting group lower alkoxyphenylmethyl, aromatic oxyphenylmethyl or alkenyloxyphenylmethyl, preferably ethoxyphenylmethyl.
  • Reaction Scheme A comprises the steps
  • Step (b) reacting the compound produced in Step (a) with acetylchloride followed by reaction with oxalyl chloride to produce a compound represented by the formula ##STR4##
  • Step (c) reacting the compound produced in Step (b) with a compound represented by the formula ##STR5## wherein R is --Si(CH 3 ) 3 or --Si(CH 3 ) 2 t--C 4 H 9 and R' is as defined for compound I, followed by reaction with anhydrous alcohol, e.g.
  • R is hydrogen, --Si(CH 3 ) 3 or --Si(CH 3 ) 2 --t--C 4 H 9
  • R' is as defined for compound I and R" is methyl, ethyl, allyl, substituted or unsubstituted phenyl wherein the substituents are R', preferably ethyl
  • Step (d) reacting the compound produced in Step (c) where R is --Si(CH 3 ) 3 with anhydrous potassium carbonate to produce a compound represented by the formula ##STR7## wherein R is hydrogen, or --Si(CH 3 ) 3 , R' is as defined for compound I and R" is as defined for compound B
  • step (e) reacting the compound produced in step (d) with pyridinium chlorochromate and anhydrous sodium acetate to produce a compound represented by the formula ##STR8## wherein R' and R" are as hereinabove defined
  • step (f) cyclizing the compound produced in step (e) by reacting with lithium hexamethyldisilazide to produce a compound represented by the formula ##STR9## wherein R' and R" are as hereinabove defined (g) deprotecting the nitrogen of the compound produced in step (f) by reacting with a dilute inorganic acid to produce a compound represented by the formula ##STR10## wherein R' is as defined hereinabove
  • a second route designated Reaction Scheme B comprises the steps of
  • step (b) reacting the compound produced in step (a) with tetra-n-butylammonium fluoride to produce a compound represented by the formula ##STR14## wherein R' and R" are as hereinabove defined
  • step (c) reacting the compound produced in step (b) with pyridinium-chlorochromate to produce a compound represented by the formula ##STR15## wherein R' and R" are as hereinabove defined
  • step (c) The compound produced in step (c) is converted to a compound of formula I as in steps (f) and (g) of Reaction Scheme A.
  • lower alkyl alone or in groups containing a lower alkyl moiety e.g. "lower alkoxy” means straight or branched chain alkyl groups having from 1 to 7 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, neopentyl, dimethyl butyl and the like. Preferred is ethyl.
  • “Lower alkenyl” means straight or branched chain alkenyl groups having from 3 to 7 carbon atoms, e.g. allyl, 2-butenyl, 3-butenyl and the like, preferred is allyl.
  • “Inert organic solvent” means an organic solvent which is non-reactive under the reaction conditions, e.g. tetrahydrofuran (THF), methylene chloride, lower alkanols, preferably methanol or ethanol, and the like.
  • THF tetrahydrofuran
  • methylene chloride methylene chloride
  • lower alkanols preferably methanol or ethanol, and the like.
  • Halogen means chlorine or bromine, preferably chlorine.
  • Readily removable nitrogen protecting group as used herein means a nitrogen protecting group which is removed from the azetidinone nitrogen under mild acidic conditions which do not affect other parts of the azetidinone molecule and do not cause any stereoisomeric changes.
  • the readily removable nitrogen protecting groups contemplated by this invention are lower alkoxy phenyl methyl groups, preferably ethoxy phenyl methyl.
  • Disposable inorganic acid means, about 0.5 to 2.0 molar hydrochloric acid, sulfuric acid or nitric acid, preferably one molar.
  • Aromaatic means phenyl or benzyl, either substituted or unsubstituted wherein the substituents are R'
  • R' and R" are as hereinabove defined
  • a preferred compound is wherein R' is hydrogen and R" is ethyl and ##STR19## wherein R' and R" are as hereinabove defined.
  • a preferred compound is wherein R' is hydrogen and R" is ethyl.
  • azetidinone represented by the formula ##STR20## wherein R' is as defined hereinabove.
  • a preferred compound is wherein R' is hydrogen.
  • the azetidinones of formula I are intermediates for producing penems and carbapenems, and are prepared by two different Reaction Schemes. In one Reaction Scheme, designated Scheme A, wherein the preferred compounds are used for illustration, L-threonine is converted to an epoxyamide which is converted to an azetidinone, then deprotected at the nitrogen, as follows: ##STR21##
  • Step (a) of Reaction Scheme A L-(-)-threonine is converted to (2S,3R) 2-bromo-3-hydroxybutyric acid by reaction with an alkali metal bromide, e.g., potassium or sodium bromide and an alkali metal nitrite, e.g., potassium or sodium nitrite, in acidic aqueous medium, preferably sulfuric acid at about 5° to 10° C. until the reaction is complete, i.e., about 30 minutes.
  • an alkali metal bromide e.g., potassium or sodium bromide
  • an alkali metal nitrite e.g., potassium or sodium nitrite
  • (2S,3R)-2-bromo-3-acetoxy-butyryl chloride is prepared by the reaction of (2S,3R)-2-bromo-3-hydroxy-butyric acid with acetyl chloride, then the reaction mixture is reacted with oxalyl chloride or thionyl chloride in an inert solvent, e.g. toluene, at cold temperature, e.g. about 0° to 10° C., under an inert atmosphere, e.g., nitrogen.
  • an inert solvent e.g. toluene
  • Step Ac (2S,3R)-2-bromo-3-acetoxy-butyryl chloride is reacted with 1-phenyl-1-trimethylsiloxyethyl-2benzaldimine in an inert solvent, e.g. dichloromethane, at cold temperatures, e.g. about 0° to 10° C. Then an anhydrous alcohol, e.g. ethanol, methanol, substituted or unsubstituted phenol or allyl alcohol, is added, followed by an organic base, e.g., pyridine or triethylamine, to neutralize the hydrogen chloride generated and the reaction is continued at room temperature, e.g. about 25° C.
  • an inert solvent e.g. dichloromethane
  • an anhydrous alcohol e.g. ethanol, methanol, substituted or unsubstituted phenol or allyl alcohol
  • organic base e.g., pyridine or triethylamine
  • Step Ad the product of Step Ac is reacted with anhydrous potassium carbonate at room temperature to produce N-(ethoxyphenylmethyl)-N-(2-hydroxy-2-phenylethyl)glycidamide.
  • Step Ae the hydroxy group is oxidized to a ketone group by reacting the compound produced in Step Ad with a mixture of pyridinium chlorochromate and anhydrous sodium acetate.
  • the reaction is conducted at room temperature until completed in about 1.5 hours as evidenced by thin layer chromatography (TLC).
  • Step Af the compound produced in Step Ae is cyclized to the azetidinone, i.e. (3S,4S)-1-(ethoxyphenylmethyl)-3-(1R-hydroxyethyl)-4-benzoyl azetidin-2-one, by reaction with a strong base, preferably lithium hexamethyldisilazide in an inert organic solvent, e.g. hexanes, at about 8°-12° C. until complete in about 1.5 hours as evidenced by TLC.
  • a strong base preferably lithium hexamethyldisilazide in an inert organic solvent, e.g. hexanes
  • Step Ag (3S,4S)-3-(1R-hydroxyethyl)-4-benzoyl-2-azetidinone is prepared from the compound of Step Af by removing the nitrogen protecting group with dilute sulfuric acid in an inert organic solvent, e.g. THF, at room temperature for about 24 hours.
  • the reaction mixture is neutralized with sodium bicarbonate and the product recovered in high yield based on the compound produced in Step Af.
  • the 1-phenyl-1-trimethylsiloxy-2-benzaldimine intermediate utilized in Step Ac is prepared by reacting the appropriately substituted 2-amino-1-phenylethanol, with bis(trimethylsilyl)acetamide at room temperature for about 3 hours in an inert organic solvent, e.g. dichloromethane.
  • an inert organic solvent e.g. dichloromethane.
  • the product thus obtained, the appropriately substituted 2-amino-1-phenyl-1-trimethylsiloxyethane is reacted with the appropriately substituted benzaldehyde for a short time, e.g. about 2 minutes, then an inert organic solvent, e.g. benzene, is added and water, which is liberated in the reaction, is removed with anhydrous magnesium sulfate.
  • a compound of formula I is prepared by reacting an analog of compound 4, i.e. wherein the trimethylsilyl group is replaced by a t-butyl dimethylsilyl group, with an oxirane butyryl chloride to produce the compound analogous to compound 6 of Reaction Scheme A, i.e. wherein the hydrogen is replaced by a t-butyl dimethyl silyl group.
  • an analog of compound 4 i.e. wherein the trimethylsilyl group is replaced by a t-butyl dimethylsilyl group
  • an oxirane butyryl chloride i.e. wherein the hydrogen is replaced by a t-butyl dimethyl silyl group.
  • Step a of Reaction Scheme B i.e. Step Ba
  • 2-amino-1-phenylethanol [prepared by the method of Dornow, Ber. 88, 1267 (1955)] is reacted in an inert organic solvent, e.g. dichloromethane, with tertiary butyl dimethylsilyl chloride followed by tetramethyl guanidine at room temperature for about 15 minutes.
  • the reaction is quenched with water to yield 2-phenyl-2-tert butyl-dimethylsiloxy-1-ethylamine.
  • Step Bb the product of Step Ba is reacted with benzaldehyde.
  • an inert organic solvent e.g. benzene
  • the water liberated in the reaction is taken up with magnesium sulfate to yield 1-phenyl-1-tertiary butyl-dimethylsiloxy 2-benzaldimine.
  • Step Bc (2R,3R)-2,3-oxirane butyryl chloride is reacted with the product of Step Bb at about 0°-10° C. in an inert organic solvent, e.g. dichloromethane. After about 30 minutes, an organic base, e.g. triethylamine or pyridine is added. An anhydrous alcohol, e.g. methanol, ethanol, phenol or allyl alcohol, preferably ethanol, is added to form the appropriate ether substituent on the phenylmethy group. When the preferred ethanol is used, the product, (2R,3R)-N-ethoxyphenyl-methyl-N-phenyl-tert butyl dimethylsiloxy-b-methylglycidamide, is made and recovered in high yields.
  • an organic solvent e.g. dichloromethane.
  • an organic base e.g. triethylamine or pyridine
  • An anhydrous alcohol e.g. methanol,
  • Step Bd the compound produced in Step Bc is deprotected at the hydroxy group by reacting the compound with tetra n-butylammonium fluoride in an inert organic solvent, e.g. THF, at room temperature until the reaction is complete in about 12 hours as evidenced by TLC.
  • an inert organic solvent e.g. THF
  • Step Be the compound produced in Step Bd is oxidized to the ketone by reaction with pyridinium chlorochromate and sodium acetate in an inert organic solvent, e.g. dichloromethane, for about 1 to 2 hours at room temperature.
  • an inert organic solvent e.g. dichloromethane
  • the compound from Step Be is converted to compound I in the same manner as in Steps Af and Ag.
  • the intermediate reactant (2R,3R)-2,3 oxirane butyrylchloride is prepared by reaction of (2S,3R)-2-bromo-3-hydroxybutyric acid and potassium hydroxide in absolute ethanol, followed by thionyl chloride in THF.
  • Acetyl chloride (6.82 g, 86.88 mmole) was added dropwise to (2S,3R)-2-bromo-3-hydroxybutyric acid (neat) with stirring.
  • the reaction mixture was cooled in a bath at 5° C. as exotherm began. After completion of addition, the cooling bath was removed. After 45 minutes the mixture was heated at 45°-50° C. for 1.5 hours. Heating was discontinued and 10 mL toluene was added.
  • the mixture was cooled in an ice bath and oxalyl chloride (11.4 80 g, 90.44 mmole) was added dropwise. After completion of addition, the mixture was allowed to warm to room temperature then heated at reflux for 30 minutes. Toluene and excess of reagents were removed by fractional distillation. The residue was subjected to bulb-to-bulb distillation at 80°-90° C. under high vacuum (1 mm/Hg) to yield the title compound.
  • step (a) herein The crude product from step (a) herein was mixed with benzaldehyde (4.452 g, 42.00 mmole). The reaction mixture was stirred for 2 minutes and benzene (50 mL) was added. The water liberated was removed by addition of anhydrous magnesium sulfate. The mixture was filtered, and the residue was washed with benzene (2 ⁇ 10 mL). The solvent was removed under reduced pressure. The product, 1-phenyl-1-trimethylsiloxy-2-benzaldimine, was subjected to high vacuum for 2 hours and used immediately for the next step.
  • benzaldehyde 4.452 g, 42.00 mmole
  • step (d) herein To a solution of the compound produced in step (d) herein in dichloromethane (25 mL) was added a powdered mixture of pyridiniumchlorochromate (13.790 g, 63.97 mmole) and anhydrous sodium acetate (3.080 g, 37.55 mmole). The suspension was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with dichloromethane (50 mL), filtered, and the filtrate concentrated in vacuo. The residue was subjected to chromatography on silica gel eluting with 35% ethyl acetate in hexanes to give the title compound.
  • step (b) 4.80 g the compound produced in step (a) was dissolved in 12 mL THF and 10 mL of a solution of tetra-n-butylammonium fluoride (1M) in THF was added. The reaction mixture was stirred at room temperature for 12 hours. This was diluted with ethyl acetate (60 mL) and washed with aqueous ammonium chloride (50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epoxy Compounds (AREA)
US06/839,307 1986-03-13 1986-03-13 Preparation of azetidinones via N-protected oxirancecarboxamide intermediates Expired - Fee Related US4740595A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US06/839,307 US4740595A (en) 1986-03-13 1986-03-13 Preparation of azetidinones via N-protected oxirancecarboxamide intermediates
EP87302092A EP0238252B1 (de) 1986-03-13 1987-03-11 Herstellung von Azetidinonen und Zwischenprodukten
ES198787302092T ES2032201T3 (es) 1986-03-13 1987-03-11 Metodo para producir azetidinonas y compuestos intermedios.
DE8787302092T DE3778946D1 (de) 1986-03-13 1987-03-11 Herstellung von azetidinonen und zwischenprodukten.
AT87302092T ATE76065T1 (de) 1986-03-13 1987-03-11 Herstellung von azetidinonen und zwischenprodukten.
JP62056399A JPS62221665A (ja) 1986-03-13 1987-03-11 アゼチジノンの製造法及び中間体
US07/127,844 US4827006A (en) 1986-03-13 1987-12-02 Preparation of azetidinones via novel protected intermediates
US07/277,084 US4963670A (en) 1986-03-13 1988-11-28 Preparation of azetidinones via novel protected intermediates
US07/621,158 US5089609A (en) 1986-03-13 1990-11-30 4-benzoyl azetidinones
GR920401693T GR3005360T3 (de) 1986-03-13 1992-08-06

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EP (1) EP0238252B1 (de)
JP (1) JPS62221665A (de)
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DE (1) DE3778946D1 (de)
ES (1) ES2032201T3 (de)
GR (1) GR3005360T3 (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4876365A (en) * 1988-12-05 1989-10-24 Schering Corporation Intermediate compounds for preparing penems and carbapenems
US5075439A (en) * 1990-08-17 1991-12-24 Pfizer Inc. Processes for (3S,4R)-3-[1(R)-t-butyl-dimethylsilyloxy)-ethyl]-4-[1-oxo-3-thiolanylthio(thiocarbonyl)thio]azetidin-2-ones and intermediates therefor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0181831A2 (de) * 1984-10-01 1986-05-21 Ciba-Geigy Ag Verfahren zur Herstellung von optisch aktiven Acyloxyazetidinonen
US4614614A (en) * 1983-03-28 1986-09-30 Ciba-Geigy Corporation Process for the manufacture of optically active azetidinones

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US4614614A (en) * 1983-03-28 1986-09-30 Ciba-Geigy Corporation Process for the manufacture of optically active azetidinones
EP0181831A2 (de) * 1984-10-01 1986-05-21 Ciba-Geigy Ag Verfahren zur Herstellung von optisch aktiven Acyloxyazetidinonen

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Title
Dornow, Berichte, vol. 88, 1267 1275 (1955). *
Dornow, Berichte, vol. 88, 1267-1275 (1955).
Hanessian, et al., JACS, vol. 107, 1438 1439 (1985). *
Hanessian, et al., JACS, vol. 107, 1438-1439 (1985).
Huffman, et al., JACS, vol. 99, 2352 2353 (1977). *
Huffman, et al., JACS, vol. 99, 2352-2353 (1977).
Izumiya, Bull. Chem., Soc. Japan, vol. 26, pp. 53 56 (1953). *
Izumiya, Bull. Chem., Soc. Japan, vol. 26, pp. 53-56 (1953).
Kronenthal, et al., J. Org. Chem., 47, 2764 2768 (1982). *
Kronenthal, et al., J. Org. Chem., 47, 2764-2768 (1982).
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Yanagisawa, et al., Tetrahedron Letters, vol. 24, No. 10, 1037-1040 (1983).

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4876365A (en) * 1988-12-05 1989-10-24 Schering Corporation Intermediate compounds for preparing penems and carbapenems
US5075439A (en) * 1990-08-17 1991-12-24 Pfizer Inc. Processes for (3S,4R)-3-[1(R)-t-butyl-dimethylsilyloxy)-ethyl]-4-[1-oxo-3-thiolanylthio(thiocarbonyl)thio]azetidin-2-ones and intermediates therefor

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EP0238252A2 (de) 1987-09-23
ATE76065T1 (de) 1992-05-15
ES2032201T3 (es) 1993-01-16
JPS62221665A (ja) 1987-09-29
EP0238252B1 (de) 1992-05-13
EP0238252A3 (en) 1987-12-02
GR3005360T3 (de) 1993-05-24
DE3778946D1 (de) 1992-06-17

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